IL26373A - 3-acetylthioethoxy and 3-acetylthiopropoxy steroids of the estrane,androstane and pregnane series,their preparation and their use - Google Patents

Description

The present invention relates to enol ethers derived from steroidal and to their More the present invention relates to 5 the Δ ethers which result from the cleavage of the 5 hemithioketal moiety of and prepared from steroidal According to the invention there is provided a process for preparing a compound having wherein R is chloro or is hydrogen or is acetyl or is lower alkyl from 1 to 8 carbon lower acyloxy from 1 to 8 carbon atoms or wherein X is chloro or lower alkyl of from 1 to 8 carbon and n is 2 wherein a compound of the formulas which and n are as above and may also be is cleaved with acetic anhydride in the presence of an acid 5 The and are prepared from steroidal by reaction with or in the presence of an acid catalyst such as A typical reaction diagram for the preparation of the Δ is as wherein R is chloro or The above described reaction is carried out according to a procedure such as that of Djerassi and It has been that the sulfur to carbon linkage of the hemithioketal moiety cleaved by treatment of the novel hemithioketals of the present invention with acetic anhydride in the presence of an acid catalyst such as 3 5 to form the corresponding Δ Typical reaction diagrams showing the cleavage of the hemithioketal are as The ethers of the present invention exhibit important pharmacological properties as antilittering agents affecting the ability of female animals to While the precise mode and of action of all of the novel compounds of the invention is not clearly it has been found that compounds of the present invention exhibit progestational The hemithioketals are of the following formulaes wherein is chloro or is hydrogen or is acetyl or is lower alkyl of from 1 to 8 carbon lower acyloxy of from 1 The novel thioenol ethers of the invention are of the following wherein is or is hydrogen or is acetyl or is lower of from 1 to 8 carbon lower acyloxy of from 1 to 8 carbon atoms or wherein X is chloro or lower alkyl of from 1 to 8 carbon atoms and n is the integer 2 or Typical steroidal from which the ketals of the present invention may be prepared testosterone ethynyltestosterone 159 testosterone testosterone testosterone testosterone testosterone acetate acetate s rone 159 acetate acetate acetate The following examples Illustrate the I A mixture of of of 500 of acid and 500 of benzene is boiled under reflux for three with constant separation of water from the oondensate by means of a After cooling to room the benzene solution Is washed with a saturated aqueous sodium bicarbonate solution and it is dried tilth anhydrous magnesium filtered and evaporated to dryness under vacuum to obtain a mixture of talline To this is added 300 of acetone and the result ing suspension is stirred and boiled gently for five It is then cooled to and filtered to remove insoluble The filtrate of material is boiled down to a volume of and this is cooled to and again filtered to insoluble The filtrate now boiled down 159 to 13 chilled to to afford of white flakes which at A second amounting to may be obtained by reworking of the mother liquor from the for C H Pound Following the procedure of Example but starting testosterone 17 17 17 and there are prepared ne 159 and EXAMPLE II A mixture of 1 of dione obtained in Example of acid and 20 of acetic anhydride is stirred vigorously at 25 for fifteen minutes and then it is cooled to and of pyridine is This mixture is poured into 500 of an ice and water mixture to which of pyridine has previously been After the precipitated oil has become partially it is separated by filtration and then dissolved in 100 of ethyl The ether solution is dried with anhydrous potassium and after filtration to remove drying agent it is reduced to a volume of 8 Storing of this concentrated ether solution at afford of yellow prisms of the desired enol Later crops of the same totalling are obtaining by further of the mother The total of of crude enol ether is now recrystallized from ethyl ether to afford of large 0 yellow prisms which melt at Calcd for Pound 237 159 Following procedure of Example but starting and hioketal there are prepared 5 and EXAMPLE III hioke A mixture acid monohydrate ORTH 159 and 15OO of benzene is boiled under reflux for one with separation of water from the condensate by of a Stark of 0 of are added and this mixture is boiled under reflux for three hours with separation of water by means of the After cooling to room the benzene solution is washed with aqueous sodium dried with anhydrous magnesium filtered and evaporated under vacuum to a residue of crude The latter is dissolve in 100 of warm acetone and this solution is chilled at to afford 0 of white Concentration and chilling of the mother liquor affords an additional as a second crystallization of this total of 20 from ethyl acetate finally affords four of white flakes which melt at for Pound 7 Following the procedure of Example but starting 159 there are prepared h and EXAMPLE IV To solution of of acid 159 monohydrate in 200 of acetic anhydride is added of obtained in Example and the mixture is stirred at for twenty The resulting clear red solution is cooled to and to it is added 50 pyridine and this mixture is then poured into 2000 of an ice and water mixture to which 600 of pyridine has previously been After the precipitated oil has become partially it is separated by filtration and then dissolved in 200 of ether solution is washed aqueous sodium bicarbonate tion and with and then it is dried with anhydrous potassium After filtration to remove drying the ether o solution is reduced to a volume of 20 and stored at 0 to effect crystallization of of the The material remaining in the ethereal mother liquor is developed onto a matographic column of acidic alumina and eluted with benzene to afford more of crude enol The bined portions of enol ether are recrystallized from ethyl ether to afford of as pale yellow prisms which melt at 122 Following the procedure of Example but starting 159 ne ne ethylenchcnithioketal ls ketal there are ΟΕ ΙΪ 159 and a1 and mixture of of 60 of and of acid in 3000 of benzene under reflux for and with constant separation of water from the densate by means of a After cooling to room the benzene solution washed with aqueous sodium solution and with and then it is dried with anhydrous magnesium filtered to remove drying and evaporated under vacuum to a viscoue The latter is developed a chromatographic column of neutral followed by ethyl affords 25 of a mixture of products which must subsequently be separated by crystallization The of mixture is boiled under reflux for two and hours with of acetic anhydride o taining 2 of pyridine and then this solution is cooled to 25 and poured of ice and water mixturo containing 30 of The oil remaining after the acetic anhydride has hydrolysed becomes crystalline on storage of the hydrolysis mixturo at for twenty The tacky is isolated by filtration and is dried in and then it is boiled in of methanol After filtration to the methanolic filtrate is allowed to 159 The which has crystallized the is filtered off and dried to afford of crude which is identified by infrared absorption This is recrystalllzed twice ethyl acetate to afford of white which at for Pound o On standing at for four the mother liquor from isolation of the deposits a further quantity of crystalline material which is isolate by filtration to afford of crude identified by its infrared absorption Further purification of this isomer effected through recrystallizatlon of its corresponding rather than the acetate which has been She of crude boiled under reflux for with 100 of methanol containing of potassium This saponification mixture is diluted with 800 of water containing 2 of acetic acid and the is extracted three small portions of methylene The combined extracts are dried anhydrous magnesium and then evaporated to a crystalline residue which is recrystalllzed from ethyl acetate to afford of white granules which melt at for Pound purified thus obtained is acetylated by boiling it under reflux for hours in 55 of acetic anhydride containing four drops of After cooling o of the acetic anhydride solution to 3 it is poured into 500 of an ice and water The crystalline solid which after hydrolysis of the acetic anhydride filtered dried and from ethyl ether to afford of white prisms which melt at for Pound A The methanollc mother liquor from the isomer has een separated and from which the has later crystallized reduced in volume to o 60 and stored at 0 for two days to effect crystallisation of of a mixture of the isomeric This materia may be subjected to the separation of Isomers detailed in part3 A and but separation is not necessary conversion to the enol The mixture may used for acetylative cleavage to the enol ether Example Following the procedure of Example but starting 159 nei and acetate there are prepared 17 l7 st 17 ene 159 cθ lenehemithioketa hemithioketa an hemithioketa EXAMPLE VI A mixture of of obtained in Example and of acid monohydrate in 20 of acetic o anhydride is stirred vigorously at 25 for one and then 5 of pyridine is added and the mixture is poured into 350 of ice and water to which 5 of pyridine has previously been The yellow solid which remains after hydrolysis of the acetic anhydride is off and dried in air and then it is recrystallized from acetone containing a few drops of pyridine to afford of cream colored flakes melt at for Pound 25 o A of obtained in and 15 of acid in 4 of acetic anhydride vigorously at for ve minutes and then the reaction mixture worked up as detailed in A with appropriate scaling down of of the crude ether affords of flakes which melt at and whose infrared spectrum is identical with that of the material obtained in 5 A mixture of of the mixture and s isolated in and of acid in 80 of acetic anhydride is stirred vigorously at 25 for minutes and then the reaction mixture is worked up as detailed in A with appropriat scaling up of of the enol ether from acetone affords of cream flakes which molt at and whose infrared is identical with that of the material obtained in the procedure of Example but starting l7 17 3 c thy tal h et e t are prepared 159 In foregoing the steroidal are reacted to form the corresponding By reacting the steroidal with the corresponding are Upon cleavage of the the corresponding compounds are insufficientOCRQuality

Claims (1)

1. CLAIMS A process for preparing a compound having the wherein R is chloro or fl is hydrogen or is acetyl or is hydrogen lower alkyl from 1 to 8 carbon lower from 1 to 8 carbon atoms or wherein X is chloro or lower alkyl of from 1 to 8 carbon and n is 2 or wherein a compound of the formulas in which and n are as above defined and may also be is cleaved with acetic anhydride in the presence of an acid A process for preparing wherein is cleaved with acetic anhydride in the presence of an acid A process for preparing wherein is cleaved with acetic anhydride in the presence of an acid A process for preparing o wherein acetox is cleaved with acetic anhydride in the presence of an acid A compound having the IV in Claim A process for preparing a compound of formula in Claim substantially as described herein with reference to the foregoing Examples 29 or A method of promoting antilittering in animals other than homo sapiens comprising administering to the animal a compound of formula IV in Claim For the Applicants insufficientOCRQuality